Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma.
ABSTRACT The N-myc downstream-regulated gene 2 (NDRG2) at 14q11.2 has been reported to be downregulated in glioblastoma, and NDRG2 overexpression represses glioblastoma cell proliferation in vitro (Deng et al., Int J Cancer 2003;106;342-7). To further address the role of NDRG2 as a candidate tumor suppressor in human gliomas, we analyzed 67 astrocytic tumors (10 diffuse astrocytomas, 11 anaplastic astrocytomas, 34 primary glioblastomas and 12 secondary glioblastomas) for NDRG2 gene mutation, promoter methylation and expression at the mRNA and protein levels. Using real-time reverse transcription PCR analysis, we found decreased NDRG2 mRNA levels in primary glioblastomas as compared to diffuse and anaplastic astrocytomas. Similarly, immunohistochemistry revealed low or absent NDRG2 protein expression in primary glioblastomas. Mutational analysis of the entire NDRG2 coding sequence did not reveal any tumor-associated DNA sequence alterations. However, sequencing of sodium bisulfite-modified DNA identified hypermethylation of the NDRG2 promoter region in 21 of 34 primary glioblastomas (62%). Moreover, NDRG2 promoter hypermethylation was associated with decreased NDRG2 mRNA expression. In contrast to primary glioblastomas, NDRG2 promoter hypermethylation was detected in only 1 of 11 anaplastic astrocytomas (9%) and was absent in 10 diffuse astrocytomas and 12 secondary glioblastomas. Taken together, our data support NDRG2 as a candidate tumor suppressor gene that is epigenetically silenced in the majority of primary glioblastomas, but not in lower grade astrocytomas and secondary glioblastomas.
Article: The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications.[show abstract] [hide abstract]
ABSTRACT: The N-myc downstream regulated gene (NDRG) family of proteins consists of 4 members, NDRG1-4, which are well conserved through evolution. The first member to be discovered and responsible for the family name was NDRG1, because its expression is repressed by the proto-oncogenes MYCN and MYC. All family members are characterized by an α/β hydrolase-fold motif; however, the precise molecular and cellular function of these family members has not been fully elucidated. Although the exact function of NDRG family members has not been clearly elucidated, emerging evidence suggests that mutations in these genes are associated with diverse neurological and electrophysiological syndromes. In addition, aberrant expression as well as tumor suppressor and oncogenic functions affecting key hallmarks of carcinogenesis such as cell proliferation, differentiation, migration, invasion, and stress response have been reported for several of the NDRG proteins. In this review, we summarize the current literature on the NDRG family members concerning their structure, origin, and tissue distribution. In addition, we review the current knowledge regarding the regulation and signaling of the NDRG family members in development and normal physiology. Finally, their role in disease and potential clinical applications (their role as detection or prognostic markers) are discussed.The FASEB Journal 11/2010; 24(11):4153-66. · 5.71 Impact Factor
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ABSTRACT: The pathological grading system of human astrocytoma is usually used to evaluate the outcomes of brain glioma patients. However, it is true that some astrocytoma patients with similar grades underwent obvious discrepancy in survival. Increasing evidence shows that certain tumor biomarkers are more suitable for prognosis assessment of tumors than the grading system. NDRG2, a member of the N-myc downstream-regulated gene family, plays an important role in cell proliferation and differentiation, but whether it can be used as a biomarker for prognosis assessment of astrocytomas remains unknown. Immunohistochemistry and semi-quantitative RT-PCR were performed to examine the expression profile of NDRG2 in human astrocytoma specimens. Spearman correlation coefficient was used to describe the association between NDRG2 expression and the clinical parameters of astrocytoma patients. Our results showed that both protein and mRNA expression levels of NDRG2 were significantly downregulated in astrocytomas. In the analysis of the relationship of NDRG2 expression with pathological grades of astrocytoma and with patient survival rate, we found that NDRG2 expression was negatively correlated with pathological grading but positively with the life span of astrocytoma patients. NDRG2 can serve as a potential prognostic biomarker for human astrocytoma.Journal of the neurological sciences 06/2011; 308(1-2):77-82. · 2.32 Impact Factor
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ABSTRACT: NDRG2, a member of the N-Myc downstream-regulated gene family, was shown to be a putative tumor suppressor gene in glioblastoma and other cancers. Through a bioinformatic analysis, we found that NDRG2 protein contains an acyl carrier domain. In the current study, we therefore hypothesized that NDRG2 may play an important role in the regulation of histone acetylation. Treatment of U251 and U87 glioma cells with trichostatin A, an inhibitor of histone deacetylase, upregulated the expression of NDRG2 and acetylated forms of histones H3 and H4, reduced tumor cell viability and arrested the cell cycle at the G1/G0 phase. Overexpression of NDRG2 by transfecting glioma cells with adenovirus containing the NDRG2 gene upregulated the levels of acetylated forms of H3 and H4 whereas inhibition of NDRG2 expression by siRNA-mediated knockdown downregulated the level of histone acetylation. Furthermore, NDRG2 siRNA significantly reduced the level of histone acetylation induced by trichostatin A. Taken together, these data demonstrate that NDRG2 can regulate the level of histone acetylation to control glioma cell growth.Journal of Neuro-Oncology 09/2011; 106(3):485-92. · 3.21 Impact Factor